ERBB2

Homo sapiens (Human)

p185erbB2; Tyrosine kinase-type cell surface receptor HER2; Receptor tyrosine-protein kinase erbB-2; Proto-oncogene c-ErbB-2; Proto-oncogene Neu; NGL; NEU; Metastatic lymph node gene 19 protein; MLN19

Protein kinase superfamily, Tyr protein kinase family, EGF receptor subfamily

Kinase

Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1 signaling pathway elicits the phosphorylation and thus the inhibition of GSK3B at cell membrane. This prevents the phosphorylation of APC and CLASP2, allowing its association with the cell membrane. In turn, membrane-bound APC allows the localization of MACF1 to the cell membrane, which is required for microtubule capture and stabilization.

Glioma (GLM) [MIM:137800]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. {ECO:0000269|PubMed:15457249}. The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Ovarian cancer (OC) [MIM:167000]: The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. {ECO:0000269|PubMed:15457249, ECO:0000269|PubMed:17344846}. The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Lung cancer (LNCR) [MIM:211980]: A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. {ECO:0000269|PubMed:15457249}. The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Gastric cancer (GASC) [MIM:613659]: A malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions, resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease. {ECO:0000269|PubMed:15457249, ECO:0000269|PubMed:17344846}. The protein represented in this entry is involved in disease pathogenesis.; DISEASE: Chromosomal aberrations involving ERBB2 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with CDK12, leading to CDK12-ERBB2 fusion leading to truncated CDK12 protein not in-frame with ERBB2. {ECO:0000269|PubMed:21097718}.; DISEASE: Visceral neuropathy, familial, 2, autosomal recessive (VSCN2) [MIM:619465]: An autosomal recessive disorder characterized by intestinal dysmotility due to aganglionosis (Hirschsprung disease), hypoganglionosis, and/or chronic intestinal pseudoobstruction. Patients also show peripheral axonal neuropathy, hypotonia, mild developmental delay, unilateral ptosis, and sensorineural hearing loss. {ECO:0000269|PubMed:33497358}. The disease is caused by variants affecting the gene represented in this entry.

DB08916; DB06021; DB12267; DB12010; DB04988; DB01259; DB14967; DB06366; DB11973; DB00072; DB05773; DB11652; DB05944; DB15035

P00519; P42684; P15309; P60709; Q92625; O00213; O75815; Q9HB71; Q16543; Q9NSE2; Q7Z7G1; P46109; Q93034; Q99704; Q8TEW6; Q15075; P98172; P00533; P04626; P21860; Q15303; Q9UJM3; P09769; P06241; O75791; P62993; Q14451; P07900; P08238; P14625; P11021; P46940; P35568; Q08881; P23458; Q14974; Q96JA1; O75367; O75367-3; Q9UQF2; Q13387; P42679; Q9Y316; O43639; Q02297-7; O00750; P27986; O00459; Q92569; P19174; P16885; O95602; Q13882; Q06124; Q05209; Q99952; Q99952-1; P23467; P08575; Q12913; Q15262; Q16827; Q15256; P49792; P20936; O95980; Q9NP31; P29353; P98077; Q92529; Q9H6Q3; O15524; P12931; P42224; P40763; P31948; Q7KZ85; P43405; Q9Y490; Q63HR2; Q68CZ2; Q96D37; P52735; O14980; P62258

EC 2.7.10.1

3D-structure; Activator; Alternative initiation; Alternative splicing; ATP-binding; Cell membrane; Cell projection; Chromosomal rearrangement; Cytoplasm; Disease variant; Disulfide bond; Endosome; Glycoprotein; Kinase; Membrane; Nucleotide-binding; Nucleus; Phosphoprotein; Proteomics identification; Receptor; Reference proteome; Signal; Transcription; Transcription regulation; Transferase; Transmembrane; Transmembrane helix; Tyrosine-protein kinase

A,B

33776.1

296

0.08

47.13

8.67

4.22

-8.23

SEC14L2

Homo sapiens (Human)

NA

KIAA1658;C22orf6;KIAA1186

NA

Transport protein

Phospholipid binding.Transporter activity.Vitamin E binding.

Neurodevelopmental disorder with poor language and loss of hand skills (NDPLHS) [MIM:617903]: An autosomal dominant disorder characterized by psychomotor developmental stagnation or regression. NDPLHS manifest in the first years of life as loss of purposeful hand movements, loss of language, and intellectual disability. {ECO:0000269|PubMed:26740508, ECO:0000269|PubMed:28856709, ECO:0000269|PubMed:29369404}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Developmental and epileptic encephalopathy 59 (DEE59) [MIM:617904]: A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE59 is an autosomal dominant condition characterized by onset of refractory seizures in early infancy. {ECO:0000269|PubMed:28856709, ECO:0000269|PubMed:29100083, ECO:0000269|PubMed:29369404}. The disease is caused by variants affecting the gene represented in this entry.

DB14003; DB14001; DB14002; DB11635; DB11251; DB00163

NA

NA

3D-structure; Activator; Alternative splicing; Cytoplasm; Lipid-binding; Nucleus; Proteomics identification; Reference proteome; Transcription; Transcription regulation; Transport

A,B

31533.3

274

0.1

49.26

8.34

2.81

-8.23

N/A

Plasmodium falciparum (isolate HB3)

NA

NA

Peptidase A1 family

Hydrolase

Aspartic-type endopeptidase activity.

Short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD) [MIM:610006]: Autosomal recessive disorder and consists of a defect in catabolism of L-isoleucine which is characterized by an increase of 2-methylbutyrylglycine and 2-methylbutyrylcarnitine in blood and urine. Affected individuals have seizures and psychomotor delay as the main clinical features. {ECO:0000269|PubMed:10832746, ECO:0000269|PubMed:11013134, ECO:0000269|PubMed:16317551}. The disease is caused by variants affecting the gene represented in this entry.

DB04378; DB04373; DB11638; DB01218; DB02505; DB03063

NA

3.4.23.39

3D-structure; Aspartyl protease; Direct protein sequencing; Disulfide bond; Hydrolase; Membrane; Protease; Reference proteome; Signal-anchor; Transmembrane; Transmembrane helix; Vacuole; Zymogen

A

36923.5

329

0.13

44.31

4.67

-17.94

-8.24

KDM1B

Homo sapiens (Human)

Lysine-specific histone demethylase 2; LSD2; Flavin-containing amine oxidase domain-containing protein 1; C6orf193; AOF1

Flavin monoamine oxidase family

CH-NH(2) donor oxidoreductase

Required for de novo DNA methylation of a subset of imprinted genes during oogenesis. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Demethylates both mono- and di-methylated 'Lys-4' of histone H3. Has no effect on tri-methylated 'Lys-4', mono-, di- or tri-methylated 'Lys-9', mono-, di- or tri-methylated 'Lys-27', mono-, di- or tri-methylated 'Lys-36' of histone H3, or on mono-, di- or tri-methylated 'Lys-20' of histone H4. Histone demethylase that demethylates 'Lys-4' of histone H3, a specific tag for epigenetic transcriptional activation, thereby acting as a corepressor.

Angioedema, hereditary, 1 (HAE1) [MIM:106100]: An autosomal dominant disorder characterized by episodic local swelling involving subcutaneous or submucous tissue of the upper respiratory and gastrointestinal tracts, face, extremities, and genitalia. Hereditary angioedema due to C1 esterase inhibitor deficiency is comprised of two clinically indistinguishable forms. In hereditary angioedema type 1, serum levels of C1 esterase inhibitor are decreased, while in type 2, the levels are normal or elevated, but the protein is non-functional. {ECO:0000269|PubMed:12773530, ECO:0000269|PubMed:1363816, ECO:0000269|PubMed:1451784, ECO:0000269|PubMed:14635117, ECO:0000269|PubMed:16409206, ECO:0000269|PubMed:2118657, ECO:0000269|PubMed:2296585, ECO:0000269|PubMed:22994404, ECO:0000269|PubMed:2365061, ECO:0000269|PubMed:24456027, ECO:0000269|PubMed:3178731, ECO:0000269|PubMed:7814636, ECO:0000269|PubMed:7883978, ECO:0000269|PubMed:8172583, ECO:0000269|PubMed:8529136, ECO:0000269|PubMed:8755917, ECO:0000269|Ref.41}. The disease is caused by variants affecting the gene represented in this entry.

NA

Q96L03

EC 1.-.-.-

3D-structure; Alternative splicing; Chromatin regulator; Chromosome; Developmental protein; FAD; Flavoprotein; Metal-binding; Nucleus; Oxidoreductase; Phosphoprotein; Proteomics identification; Reference proteome; Repressor; Transcription; Transcription regulation; Zinc; Zinc-finger

A,C

85795.5

763

0.1

37.87

8.41

9.16

-8.24

H3F3A

Homo sapiens (Human)

PP781; Histone H3.3; H3F3; H3.3B; H3.3A

Histone H3 family

NA

Variant histone H3 which replaces conventional H3 in a wide range of nucleosomes in active genes. Constitutes the predominant form of histone H3 in non-dividing cells and is incorporated into chromatin independently of DNA synthesis. Deposited at sites of nucleosomal displacement throughout transcribed genes, suggesting that it represents an epigenetic imprint of transcriptionally active chromatin. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.

Glioma (GLM) [MIM:137800]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. {ECO:0000269|PubMed:22286061, ECO:0000269|PubMed:22286216, ECO:0000269|PubMed:23539269}. The gene represented in this entry is involved in disease pathogenesis. H3F3A mutations affecting residues involved in post-translational modifications of histone H3.3 are recurrent in malignant, aggressive gliomas including glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG) (PubMed:22286061, PubMed:22286216). The mechanism through which mutations lead to tumorigenesis involves altered histones methylation, impaired regulation of Polycomb repressive complex 2 (PRC2) activity, and aberrant epigenetic regulation of gene expression (PubMed:23539183, PubMed:23539269, PubMed:23603901). {ECO:0000269|PubMed:22286061, ECO:0000269|PubMed:22286216, ECO:0000269|PubMed:23539183, ECO:0000269|PubMed:23539269, ECO:0000269|PubMed:23603901}.; DISEASE: Bryant-Li-Bhoj neurodevelopmental syndrome 1 (BRYLIB1) [MIM:619720]: An autosomal dominant disorder predominantly characterized by global developmental delay, impaired intellectual development, poor or absent speech, and delayed motor milestones. Clinical manifestations are highly variable, including abnormal head shape, dysmorphic facial features, oculomotor abnormalities, feeding problems, and non-specific brain imaging abnormalities. Additional features may include hearing loss, seizures, short stature, and mild skeletal defects. {ECO:0000269|PubMed:33268356, ECO:0000269|PubMed:34876591}. The disease is caused by variants affecting the gene represented in this entry. BRYLIB1 is caused by variants in H3-3A. {ECO:0000269|PubMed:33268356, ECO:0000269|PubMed:34876591}.; DISEASE: Bryant-Li-Bhoj neurodevelopmental syndrome 2 (BRYLIB2) [MIM:619721]: An autosomal dominant disorder predominantly characterized by global developmental delay, impaired intellectual development, poor or absent speech, and delayed motor milestones. Clinical manifestations are highly variable, including abnormal head shape, dysmorphic facial features, oculomotor abnormalities, feeding problems, and non-specific brain imaging abnormalities. Additional features may include hearing loss, seizures, short stature, and mild skeletal defects. {ECO:0000269|PubMed:33268356, ECO:0000269|PubMed:34876591}. The disease is caused by variants affecting the gene represented in this entry. BRYLIB2 is caused by variants in H3-3B. {ECO:0000269|PubMed:33268356, ECO:0000269|PubMed:34876591}.; DISEASE: H3F3A and H3F3B mutations affecting residues involved in post-translational modifications of histone H3.3 are implicated in the pathogenesis of some bone and cartilage neoplasms. Mutations have been found with high prevalence in chondroblastoma and giant cell tumors of bone, and with low frequency in osteosarcoma, conventional chondrosarcoma and clear cell chondrosarcoma. Chondroblastoma samples frequently carry a H3F3B mutation affecting residue Lys-37 (H3K36), although H3F3A is mutated in some cases. Most giant cell tumors of bone harbor H3F3A mutations affecting residue Gly-35 (H3G34). {ECO:0000269|PubMed:24162739}.

NA

Q9NVP2; P45973; Q13111; Q9UER7; Q9UER7-1; Q9Y6K1; P62805; P49321-2; Q8IZL8; Q5VWG9; Q9VK33; Q8R5C8

NA

3D-structure; Acetylation; ADP-ribosylation; Chromosome; Citrullination; Direct protein sequencing; Disease variant; DNA-binding; Hydroxylation; Intellectual disability; Lipoprotein; Methylation; Nucleosome core; Nucleus; Phosphoprotein; Proteomics identification; Reference proteome; Ubl conjugation

A,C

86148.9

766

0.1

37.57

8.25

7.16

-8.23

MAP2K2

Homo sapiens (Human)

PRKMK2; MKK2; MEK 2; MAPKK 2; MAPK/ERK kinase 2; MAP kinase kinase 2; Dual specificity mitogenactivated protein kinase kinase 2; Dual specificity mitogen-activated protein kinase kinase 2

Protein kinase superfamily, STE Ser/Thr protein kinase family, MAP kinase kinase subfamily

Kinase

Activates the ERK1 and ERK2 MAP kinases. Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases.

Cardiofaciocutaneous syndrome 4 (CFC4) [MIM:615280]: A form of cardiofaciocutaneous syndrome, a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and intellectual disability. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. {ECO:0000269|PubMed:16439621, ECO:0000269|PubMed:18042262, ECO:0000269|PubMed:20358587}. The disease is caused by variants affecting the gene represented in this entry.

DB11967; DB06616; DB12010; DB14904; DB11689; DB08911

P05067; P10398; Q96II5; P15056; O95273; Q12959; P61978-2; Q8IVT5; P00540; P04049

EC 2.7.12.2

3D-structure; Acetylation; ATP-binding; Cardiomyopathy; Cytoplasm; Direct protein sequencing; Disease variant; Ectodermal dysplasia; Intellectual disability; Kinase; Magnesium; Membrane; Metal-binding; Nucleotide-binding; Phosphoprotein; Proteomics identification; Reference proteome; Serine/threonine-protein kinase; Transferase; Tyrosine-protein kinase

A

33960.9

303

0.07

45.61

6.29

-2.53

-8.23

cpo

Kitasatospora aureofaciens (Streptomyces aureofaciens)

NA

cpoT

AB hydrolase superfamily, Bacterial non-heme haloperoxidase / perhydrolase family

Haloperoxidase

Chloride peroxidase activity.

Hypervalinemia and hyperleucine-isoleucinemia (HVLI) [MIM:618850]: An autosomal recessive metabolic disorder characterized by highly elevated plasma concentrations of valine and leucine/isoleucine. Affected individuals suffer from headache and mild memory impairment. {ECO:0000269|PubMed:25653144}. The disease is caused by variants affecting the gene represented in this entry. A patient with hypervalinemia and hyperleucine-isoleucinemia was identified as compound heterozygote for Gln-170 (inherited from his father) and Lys-264 (inherited from his mother), both variants reduced the catalytic activity of the enzyme. After treatment with vitamin B6, a precursor of pyridoxal 5'-phosphate, a BCAT2 cofactor, the blood levels of branched chain amino acids, especially valine, were decreased and brain lesions were improved. {ECO:0000269|PubMed:25653144}.

DB03793

NA

1.11.1.-

3D-structure; Chloride; Oxidoreductase; Peroxidase

A,B

60428.4

554

0.13

31.26

4.65

-32.72

-8.23

fpr

Escherichia coli (strain K12)

NA

mvrA;b3924;JW3895

Ferredoxin--NADP reductase type 1 family

Flavoprotein

FAD binding.Ferredoxin-NADP+ reductase activity.Oxidoreductase activity.

Noonan syndrome 13 (NS13) [MIM:619087]: A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. NS13 inheritance is autosomal dominant. There is considerable variability in severity. {ECO:0000269|PubMed:32721402}. The disease is caused by variants affecting the gene represented in this entry.

DB03147

NA

1.18.1.2; 1.19.1.1

3D-structure; Cytoplasm; Direct protein sequencing; FAD; Flavoprotein; NADP; Nucleotide-binding; Oxidoreductase; Reference proteome

A

27346.2

244

0.08

30.68

7.25

0.42

-8.22

AOC1

Homo sapiens (Human)

Kidney amine oxidase; KAO; Histaminase; Amiloride-binding protein; AOC1; ABP

Copper/topaquinone oxidase family

CH-NH(2) donor oxidoreductase

Catalyzes the degradation of compounds such as putrescine, histamine, spermine, and spermidine, substances involved in allergic and immune responses, cell proliferation, tissue differentiation, tumor formation, and possibly apoptosis. Placental DAO is thought to play a role in the regulation of the female reproductive function.

Lichtenstein-Knorr syndrome (LIKNS) [MIM:616291]: An autosomal recessive neurologic disorder characterized by progressive cerebellar ataxia and severe progressive sensorineural hearing loss. {ECO:0000269|PubMed:25205112, ECO:0000269|PubMed:30237576}. The disease is caused by variants affecting the gene represented in this entry.

DB00594; DB01373; DB09130; DB03608; DB05383

Q15038; O75593; Q8IUC2; Q96HA8; Q7Z3K3; Q6ZRY4; Q01085-2; O43711; Q96K80

EC 1.4.3.22

3D-structure; Alternative splicing; Calcium; Cell membrane; Copper; Direct protein sequencing; Disulfide bond; Glycoprotein; Heparin-binding; Membrane; Metal-binding; Oxidoreductase; Proteomics identification; Reference proteome; Secreted; Signal; TPQ

A,B

69037.3

607

0.13

43.33

6.52

-4.61

-8.22

HNMT

Homo sapiens (Human)

Histamine-N-methyltransferase; HNMT; HMT

Class I-like SAM-binding methyltransferase superfamily, HNMT family

Methyltransferase

Inactivates histamine by N-methylation. Plays an important role in degrading histamine and in regulating the airway response to histamine.

Intellectual developmental disorder, autosomal recessive 51 (MRT51) [MIM:616739]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:26206890}. The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry.

DB00613; DB13875; DB05381; DB04655; DB01103; DB01752; DB07106

NA

EC 2.1.1.8

3D-structure; Alternative splicing; Cytoplasm; Disease variant; Intellectual disability; Methyltransferase; Proteomics identification; Reference proteome; S-adenosyl-L-methionine; Transferase

A,B

32712

288

0.1

36.38

5.18

-9.97

-8.23

SEC14L4

Homo sapiens (Human)

NA

TAP3

NA

Transport protein

Lipid binding.Transporter activity.

Chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia (CDP-PBHM) [MIM:300863]: A disease characterized by chondrodysplasia, severe platyspondyly, hydrocephaly, and facial features with microphthalmia. Bone abnormalities include a distinctive metaphyseal cupping of the metacarpals, metatarsals, and phalanges. Affected females show a milder phenotype with small stature, sometimes associated with body asymmetry and mild intellectual disability. {ECO:0000269|PubMed:20181727}. The disease is caused by variants affecting the gene represented in this entry.

DB14003; DB11635; DB11251; DB00163

Q96LC9; O43186; P78358; Q9NYQ3; Q0VD86; Q15323; O76011; P50221; Q6FHY5; Q02548; P26367; Q9H8W4; Q04864; Q04864-2; Q9UHV2; P15884; P15884-3; Q96N21; Q9BYV2; Q8N6Y0; Q9H0C1

NA

3D-structure; Alternative splicing; Lipid-binding; Proteomics identification; Reference proteome; Transport

A,B

23947.6

210

0.1

50.84

5.55

-3.11

-8.22

TRBC1

Homo sapiens (Human)

TCRBC1; BV05S1J2.2

NA

NA

Alpha-beta T cell receptors are antigen specific receptors which are essential to the immune response and are present on the cell surface of T lymphocytes. Recognize peptide-major histocompatibility (MH) (pMH) complexes that are displayed by antigen presenting cells (APC), a prerequisite for efficient T cell adaptive immunity against pathogens. Binding of alpha-beta TR to pMH complex initiates TR-CD3 clustering on the cell surface and intracellular activation of LCK that phosphorylates the ITAM motifs of CD3G, CD3D, CD3E and CD247 enabling the recruitment of ZAP70. In turn, ZAP70 phosphorylates LAT, which recruits numerous signaling molecules to form the LAT signalosome. The LAT signalosome propagates signal branching to three major signaling pathways, the calcium, the mitogen-activated protein kinase (MAPK) kinase and the nuclear factor NF-kappa-B (NF-kB) pathways, leading to the mobilization of transcription factors that are critical for gene expression and essential for T cell growth and differentiation. The T cell repertoire is generated in the thymus, by V-(D)-J rearrangement. This repertoire is then shaped by intrathymic selection events to generate a peripheral T cell pool of self-MH restricted, non-autoaggressive T cells. Post-thymic interaction of alpha-beta TR with the pMH complexes shapes TR structural and functional avidity. Constant region of T cell receptor (TR) alpha chain.

Immunodeficiency 57 with autoinflammation (IMD57) [MIM:618108]: An autosomal recessive primary immunodeficiency characterized by lymphopenia and recurrent viral, bacterial, and fungal infections. Patients exhibit early-onset inflammatory bowel disease involving the upper and lower gastrointestinal tract, and develop progressive polyarthritis. {ECO:0000269|PubMed:30026316}. The disease is caused by variants affecting the gene represented in this entry. RIPK1-deficient immune cells from IMD57 patients have impaired proinflammatory signaling leading to dysregulated cytokine secretion and are prone to necroptosis. {ECO:0000269|PubMed:30026316}.; DISEASE: Autoinflammation with episodic fever and lymphadenopathy (AIEFL) [MIM:618852]: An autosomal dominant immunologic disorder characterized by early onset of recurrent episodes of unexplained fever, lymphadenopathy, hepatosplenomegaly, and increased levels of inflammatory cytokines and chemokines in patient serum. {ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:31827281}. The disease is caused by variants affecting the gene represented in this entry.

DB02740

NA

NA

3D-structure; Adaptive immunity; Cell membrane; Disulfide bond; Glycoprotein; Immunity; Immunoglobulin domain; Membrane; Proteomics identification; Receptor; Reference proteome; T cell receptor; Transmembrane; Transmembrane helix

C,B,A

84668.2

736

0.13

39.96

5.8

-14.36

-8.22

RARA

Homo sapiens (Human)

RAR-alpha; RAR alpha; Nuclear receptor subfamily 1 group B member 1; NR1B1

Nuclear hormone receptor family, NR1 subfamily

Nuclear hormone receptor

Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis. Has a role in the survival of early spermatocytes at the beginning prophase of meiosis. In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function. Receptor for retinoic acid.

Chromosomal aberrations involving RARA are commonly found in acute promyelocytic leukemia. Translocation t(11;17)(q32;q21) with ZBTB16/PLZF; translocation t(15;17)(q21;q21) with PML; translocation t(5;17)(q32;q11) with NPM. The PML-RARA oncoprotein requires both the PML ring structure and coiled-coil domain for both interaction with UBE2I, nuclear microspeckle location and sumoylation. In addition, the coiled-coil domain functions in blocking RA-mediated transactivation and cell differentiation. {ECO:0000269|PubMed:12691149, ECO:0000269|PubMed:8302850, ECO:0000269|PubMed:8562957}.

DB00459; DB00210; DB00523; DB00926; DB00982; DB05785; DB04942; DB00799; DB00755; DB12808

O43707-1; O15296; Q15699; Q96RK4; O95273; P51946; Q15910; P50148; Q9UKP3; Q96EZ8; Q15648; Q71SY5; Q15788; Q9Y6Q9; O75376; Q9Y618; Q16236; P13056-2; P48552; Q9UPP1-2; Q9H8W4; P37231; P78527; P19793; P28702; P28702-3; P48443; Q96EB6; P63165; Q8WW24; Q2M1K9; Q91XC0; P59598; Q14457; P48552; Q96CV9; P28702; P48443; Q8WW24

NA

3D-structure; Alternative splicing; Chromosomal rearrangement; Cytoplasm; DNA-binding; Isopeptide bond; Metal-binding; Nucleus; Phosphoprotein; Proteomics identification; Proto-oncogene; Receptor; Reference proteome; Transcription; Transcription regulation; Ubl conjugation; Zinc; Zinc-finger

A

27724.1

244

0.05

50.8

5.82

-3.61

-8.21

VDR

Homo sapiens (Human)

Vitamin D(3) receptor; Nuclear vitamin D receptor; Nuclear receptor subfamily 1 group I member 1; NR1I1; 1,25-dihydroxyvitamin D3 receptor

Nuclear hormone receptor family, NR1 subfamily

Nuclear hormone receptor

Enters the nucleus upon vitamin D3 binding where it forms heterodimers with the retinoid X receptor/RXR. The VDR-RXR heterodimers bind to specific response elements on DNA and activate the transcription of vitamin D3-responsive target genes. Plays a central role in calcium homeostasis. Nuclear receptor for calcitriol, the active form of vitamin D3 which mediates the action of this vitamin on cells.

Rickets vitamin D-dependent 2A (VDDR2A) [MIM:277440]: A disorder of vitamin D metabolism resulting in severe rickets, hypocalcemia and secondary hyperparathyroidism. Most patients have total alopecia in addition to rickets. {ECO:0000269|PubMed:1652893, ECO:0000269|PubMed:17970811, ECO:0000269|PubMed:2177843, ECO:0000269|PubMed:2849209, ECO:0000269|PubMed:28698609, ECO:0000269|PubMed:7828346, ECO:0000269|PubMed:8106618, ECO:0000269|PubMed:8381803, ECO:0000269|PubMed:8392085, ECO:0000269|PubMed:8675579, ECO:0000269|PubMed:8961271, ECO:0000269|PubMed:9005998}. The disease is caused by variants affecting the gene represented in this entry.

DB07530; DB08742; DB01436; DB04891; DB00146; DB02300; DB00136; DB00169; DB04540; DB05024; DB11672; DB14635; DB01070; DB06410; DB05295; DB06194; DB00153; DB04796; DB03451; DB00910; DB04258; DB11094

P35222; Q09472; Q15648; P50222; Q15788; P26045; P19793; Q13573; Q13501; P04637; Q15645; Q9JLI4; P28700; X5D778; Q96HA8; Q01804; Q96S38; P48443

NA

3D-structure; Alternative splicing; Cytoplasm; Disease variant; DNA-binding; Metal-binding; Nucleus; Proteomics identification; Receptor; Reference proteome; Transcription; Transcription regulation; Ubl conjugation; Zinc; Zinc-finger

A

28781

254

0.07

47.69

6.15

-3.44

-8.21

BBOX1

Homo sapiens (Human)

NA

BBH;BBOX

Gamma-BBH/TMLD family

Oxidoreductase

Gamma-butyrobetaine dioxygenase activity.Identical protein binding.Iron ion binding.Zinc ion binding.

Neurodevelopmental disorder with poor language and loss of hand skills (NDPLHS) [MIM:617903]: An autosomal dominant disorder characterized by psychomotor developmental stagnation or regression. NDPLHS manifest in the first years of life as loss of purposeful hand movements, loss of language, and intellectual disability. {ECO:0000269|PubMed:26740508, ECO:0000269|PubMed:28856709, ECO:0000269|PubMed:29369404}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Developmental and epileptic encephalopathy 59 (DEE59) [MIM:617904]: A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE59 is an autosomal dominant condition characterized by onset of refractory seizures in early infancy. {ECO:0000269|PubMed:28856709, ECO:0000269|PubMed:29100083, ECO:0000269|PubMed:29369404}. The disease is caused by variants affecting the gene represented in this entry.

DB00126

O75936; A0MZ66-7

1.14.11.1

3D-structure; Carnitine biosynthesis; Cytoplasm; Dioxygenase; Iron; Metal-binding; Oxidoreductase; Phosphoprotein; Proteomics identification; Reference proteome; Zinc

A

31642.5

275

0.12

35.68

6.33

-2.46

-8.22

NQO1

Homo sapiens (Human)

Qui reductase 1; QR1; Phylloquinone reductase; Phylloqui reductase; NMOR1; NAD(P)H:quinone oxidoreductase 1; NAD(P)H dehydrogenase [quinone] 1; Menadione reductase; DTD; DT-diaphorase 1; DT-diaphorase

NAD(P)H dehydrogenase (quinone) family

NADH/NADPH oxidoreductase

The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinons involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis.

Congenital disorder of glycosylation 2D (CDG2D) [MIM:607091]: A multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. {ECO:0000269|PubMed:11901181, ECO:0000269|PubMed:30653653, ECO:0000269|PubMed:32157688}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Combined low LDL and fibrinogen (CLDLFIB) [MIM:620364]: An autosomal recessive condition characterized by low plasma LDL-cholesterol and fibrinogen levels, and associated with a decreased risk of coronary artery disease. {ECO:0000269|PubMed:34855475}. Disease susceptibility may be associated with variants affecting the gene represented in this entry.

DB07385; DB02395; DB03626; DB14001; DB04392; DB09061; DB00958; DB02633; DB00515; DB14002; DB00266; DB00997; DB01927; DB02400; DB03147; DB00170; DB00526; DB00252; DB04090; DB00163

P07902; Q9UK53; P15559

EC 1.6.5.2

3D-structure; Alternative splicing; Cytoplasm; FAD; Flavoprotein; Isopeptide bond; NAD; NADP; Oxidoreductase; Phosphoprotein; Proteomics identification; Reference proteome; Ubl conjugation

A,B,C,D

61454.1

546

0.12

36.74

8.99

8.99

-8.21

Bact hmp

Escherichia coli (strain K12)

Nitric oxide dioxygenase; NOD; NO oxygenase; Hemoglobin-like protein; HMP; Ferrisiderophore reductase B; Dihydropteridine reductase

Globin family, Two-domain flavohemoproteins subfamily; Flavoprotein pyridine nucleotide cytochrome reductase family

Paired donor oxygen oxidoreductase

Various electron acceptors arealso reduced by HMP in vitro, including dihydropterine, ferrisiderophores, ferric citrate, cytochrome c, nitrite, S-nitrosoglutathione, and alkylhydroperoxides. However, it is unknown if these reactions are of any biological significance in vivo.

Ovarian dysgenesis 1 (ODG1) [MIM:233300]: An autosomal recessive disease characterized by primary amenorrhea, variable development of secondary sex characteristics, poorly developed streak ovaries, and high serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). {ECO:0000269|PubMed:10551778, ECO:0000269|PubMed:11889179, ECO:0000269|PubMed:12571157, ECO:0000269|PubMed:12915623, ECO:0000269|PubMed:7553856, ECO:0000269|PubMed:9769327, ECO:0000269|PubMed:9851774}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Ovarian hyperstimulation syndrome (OHSS) [MIM:608115]: Disorder which occurs either spontaneously or most often as an iatrogenic complication of ovarian stimulation treatments for in vitro fertilization. The clinical manifestations vary from abdominal distention and discomfort to potentially life-threatening, massive ovarian enlargement and capillary leak with fluid sequestration. Pathologic features of this syndrome include the presence of multiple serous and hemorrhagic follicular cysts lined by luteinized cells, a condition called hyperreactio luteinalis. {ECO:0000269|PubMed:12930927, ECO:0000269|PubMed:12930928, ECO:0000269|PubMed:15080154, ECO:0000269|PubMed:16278261, ECO:0000269|PubMed:17721928, ECO:0000269|PubMed:24058690, ECO:0000269|PubMed:25581598}. The disease is caused by variants affecting the gene represented in this entry.

DB03147

NA

EC 1.14.12.17

3D-structure; Cytoplasm; Detoxification; Direct protein sequencing; FAD; Flavoprotein; Heme; Iron; Metal-binding; NAD; NADP; Oxidoreductase; Oxygen transport; Reference proteome; Transport

A

43867.1

396

0.1

28.85

5.48

-12.32

-8.21

PFF0160c

Plasmodium falciparum (isolate 3D7)

NA

NA

Dihydroorotate dehydrogenase family, Type 2 subfamily

Oxidoreductase

Dihydroorotate dehydrogenase activity.

Combined oxidative phosphorylation deficiency 33 (COXPD33) [MIM:617713]: An autosomal recessive disorder caused by multiple mitochondrial respiratory chain defects and impaired mitochondrial energy metabolism. Clinical manifestations are highly variable. Affected infants present with cardiomyopathy accompanied by multisystemic features involving liver, kidney, and brain. Death in infancy is observed in some patients. Children and adults present with myopathy and progressive external ophthalmoplegia. {ECO:0000269|PubMed:28942965}. The disease is caused by variants affecting the gene represented in this entry.

DB01117

NA

1.3.5.2

3D-structure; Flavoprotein; FMN; Membrane; Mitochondrion; Mitochondrion inner membrane; Oxidoreductase; Pyrimidine biosynthesis; Reference proteome; Transit peptide; Transmembrane; Transmembrane helix

A,B

42573.5

378

0.1

36.63

8.21

3.17

-8.21

cocE

Rhodococcus sp. (strain MB1 Bresler)

NA

NA

CocE/NonD hydrolase family

Hydrolase

Carboxylic ester hydrolase activity.Dipeptidyl-peptidase activity.

Thiamine metabolism dysfunction syndrome 5, episodic encephalopathy type (THMD5) [MIM:614458]: An autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes result in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases may result in loss of ability to walk. Cognitive function is usually preserved, although mildly delayed development has been reported. These episodes are usually associated with infection and metabolic decompensation. Some patients may have recovery of some neurologic deficits. {ECO:0000269|PubMed:22152682}. The disease is caused by variants affecting the gene represented in this entry.

DB03793; DB01795

NA

3.1.1.84

3D-structure; Cytoplasm; Direct protein sequencing; Hydrolase; Serine esterase

A

62127.9

574

0.09

26.62

4.56

-33.24

-8.22

KMT5B

Homo sapiens (Human)

Lysine N-methyltransferase 5B; Lysine-specific methyltransferase 5B; Suppressor of variegation 4-20 homolog 1; Su(var)4-20 homolog 1; Suv4-20h1; [histone H4]-N-methyl-L-lysine20 N-methyltransferase KM

Class V-like SAM-binding methyltransferase superfamily, Histone-lysine methyltransferase family, Suvar4-20 subfamily

NA

Histone methyltransferase that specifically methylates monomethylated 'Lys-20' (H4K20me1) and dimethylated 'Lys-20' (H4K20me2) of histone H4 to produce respectively dimethylated 'Lys-20' (H4K20me2) and trimethylated 'Lys-20' (H4K20me3) and thus regulates transcription and maintenance of genome integrity. In vitro also methylates unmodified 'Lys-20' (H4K20me0) of histone H4 and nucleosomes. H4 'Lys-20' trimethylation represents a specific tag for epigenetic transcriptional repression. Mainly functions in pericentric heterochromatin regions, thereby playing a central role in the establishment of constitutive heterochromatin in these regions. KMT5B is targeted to histone H3 via its interaction with RB1 family proteins (RB1, RBL1 and RBL2) (By similarity). Plays a role in myogenesis by regulating the expression of target genes, such as EID3. Facilitates TP53BP1 foci formation upon DNA damage and proficient non-homologous end-joining (NHEJ)-directed DNA repair by catalyzing the di- and trimethylation of 'Lys-20' of histone H4. May play a role in class switch reconbination by catalyzing the di- and trimethylation of 'Lys-20' of histone H4 (By similarity).

Intellectual developmental disorder, autosomal dominant 51 (MRD51) [MIM:617788]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:28191889, ECO:0000269|PubMed:29276005}. The disease is caused by variants affecting the gene represented in this entry.

NA

Q9H2G4; Q61026

EC 2.1.1.361

3D-structure; Alternative splicing; Chromatin regulator; Chromosome; Disease variant; Intellectual disability; Isopeptide bond; Metal-binding; Methyltransferase; Myogenesis; Nucleus; Proteomics identification; Reference proteome; Repressor; S-adenosyl-L-methionine; Transcription; Transcription regulation; Transferase; Ubl conjugation; Zinc

A

26230.2

233

0.11

42.29

5.64

-6.07

-8.21